Curcumin binds tubulin, induces mitotic catastrophe, and impedes normal endothelial cell proliferation

Abstract

Curcumin, a component of turmeric spice that imparts flavor and color to curry, is thought to possess anti-inflammatory and antioxidant properties in biological tissues. However, while such efficacies have been described in the context of carcinogenesis, the impact of curcumin on normal cell cycle regulation is poorly understood. Here, we provide evidence of curcumin toxicity in proliferating bovine aortic endothelial cells, at concentrations relevant to the diet and below those previously reported in cancer models. Upon confirming curcumin’s ability to upregulate hemeoxygenase-1 in a dose-dependent fashion, we found the minimally efficacious curcumin concentration to also inhibit endothelial cell DNA synthesis. Moreover, curcumin concentrations below the minimum 2 µM threshold required to induce hemeoxy-genase-1 bound tubulin protein in vitro and triggered hallmark evidence of mitotic catastrophe in vivo. Concentrations as low as 0.1 µM curcumin led to disproportionate DNA segregation, karyorrhexis, and micronucleation in proliferating endothelial cells. While suggesting a mechanism by which physiological curcumin concentrations inhibit cell cycle progression, these findings describe heretofore unappreciated curcumin toxicity with potential implications for endothelial growth, development, and tissue healing.

Phytonutrients Differentially Stimulate NAD(P)H:Quinone Oxidoreductase, Inhibit Proliferation, and Trigger Mitotic Catastrophe in Hepa1c1c7 Cells

“…More importantly, however, sulforaphane and curcumin stimulated the NQO1 activity without disrupting hepatic cell cycle progression and at concentrations likely achievable in plasma or serum following oral administration. 39,40 Furthermore, in light of our recent report describing the impact of relatively low curcumin concentrations on endothelial cell mitotic progression, 32 sulforaphane is now emerging as perhaps a superior phytonutrient with regard to safe stimulation of Phase II detoxification. Sulforaphane clearly induces hepatic NQO1 at concentrations far below those shown to bind tubulin protein, 28 depolymerize cellular microtubules, 29 or otherwise lead to biomarkers of mitotic catastrophe.…”

“…Samples were then spun onto slides, stained with WrightGiemsa dye, and examined for evidence of mitotic catastrophe as previously described. 32 …”

“…30,31 Evidence of similar toxicity exists for curcumin, quercetin, and resveratrol, where these phytonutrients have each been reported to impact cell cycle regulation (and lead to biomarkers of cell death) in various experimental models. [32][33][34] However, rigorous dose-response comparisons identifying specific outcomes of phytonutrient efficacy versus toxicity within a common experimental model have not yet been described. Given that phytonutrients may bind with proteins other than Keap1, 28 cells could be more sensitive to phytonutrient-induced cell cycle disruptions, compared with the respective minimum threshold concentrations triggering Nrf2/ARE pathway activation.…”

Synthesis, crystal structure and DFT studies of a dual fluorescent ketamine: Structural changes in the ground and excited states

“…Dibenzoylmethane (DBM), a bioactive β-diketone structurally related to curcumin, is a minor constituent of licorice. It possesses anticarcinogenic, antitumorigenic and chemopreventive activities and used as antiestrogenic drug [1][2][3][4][5][6][7][8][9]. The keto-enol tautomerism in DBM is responsible for the strongest quinone reductase (QR) inductive activity against Hepa 1c1c7 cell system [10][11][12].…”

“…The L tautomerizes as ketamine (KHB), enolimine (EHB) and ketoimine (KI) forms (Scheme 1). The fluorophore was characterized by IR, 1 The excitation energies were obtained at TD-DFT level in different solvents [29].…”